Alcohol abuse is the major risk factor for pancreatitis. It has been shown that the drinking pattern affects the impact of alcohol-induced organ damage. However, the underlying cellular and molecular mechanisms remain unclear. The progress in this line of research has been hindered by the lack of appropriate animal models. We have recently developed a paradigm of chronic plus binge alcohol exposure in which alcohol caused pancreatic damage characteristic of acute pancreatitis. We showed neither chronic nor binge alcohol exposure alone caused significant pancreatic damage. However, chronic plus binge alcohol exposure induced drastic pancreatic damage and inflammation which was accompanied by endoplasmic reticulum (ER) stress. ER is the site for protein folding, modification and transport, and calcium storage. ER stress is caused by the alterations in ER homeostasis, such as increased protein synthesis, accumulation of misfolded proteins, or changes in the calcium levels. ER stress triggers unfolded protein response (UPR) which functions to restore ER homeostasis. However, sustained ER stress exceeds UPR?s ability to restore ER homeostasis, resulting in cell death. We further showed that chronic alcohol exposure inhibited the expression of MANF, a key ER stress responsive protein which was originally identified as a neurotrophic factor and functions primarily to maintain ER homeostasis. We hypothesize that MANF is a critical UPR component that can alleviate ER stress in response to alcohol exposure, and chronic alcohol exposure impairs MANF, resulting in increased susceptibility to ER stress. We propose two specific aims to test these hypotheses. Specific Aim 1 determines the role of MANF in chronic/binge alcohol exposure-induced damage to the pancreas. Specific Aim 2 determines whether ER stress plays a critical role in chronic/binge alcohol exposure-induced damage to the pancreas. As a unit, the proposal will use novel animal models to investigate the mechanisms underlying chronic/binge alcohol exposure-induced pancreatic damage. The study will not only gain insight into cellular/molecular mechanisms of alcoholic pancreatitis but also establish a protective role of MANF. It therefore may offer a potential new therapeutic target for the treatment of alcoholic pancreatitis.